Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

Lin, Wei; Mandal, Soma; Degen, David; Liu, Yu; Ebright, Yon W.; Li, Shengjian; Feng, Yu; Zhang, Yu; Mandal, Sukhendu; Jiang, Yi; Liu, Shuang; Gigliotti, Matthew; Talaue, Meliza; Connell, Nancy; Das, Kalyan; Arnold, Eddy; Ebright, Richard H.

doi:10.1016/j.molcel.2017.03.001

Title: Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

Journal Article · Thu Apr 06 00:00:00 EDT 2017 · Molecular Cell

DOI:https://doi.org/10.1016/j.molcel.2017.03.001· OSTI ID:1368240

Lin, Wei ^[1]; Mandal, Soma ^[1]; Degen, David ^[1]; Liu, Yu ^[1]; Ebright, Yon W. ^[1]; Li, Shengjian ^[1]; Feng, Yu ^[1]; Zhang, Yu ^[2]; Mandal, Sukhendu ^[1]; Jiang, Yi ^[1]; Liu, Shuang ^[1]; Gigliotti, Matthew ^[1]; Talaue, Meliza ^[3]; Connell, Nancy ^[3]; Das, Kalyan ^[4]; Arnold, Eddy ^[1]; Ebright, Richard H. ^[1]

Rutgers Univ., Piscataway, NJ (United States)
Rutgers Univ., Piscataway, NJ (United States); Chinese Academy of Sciences (CAS), Shanghai (China)
Rutgers Univ., Newark, NJ (United States). New Jersey Medical School
Rutgers Univ., Piscataway, NJ (United States); Katholieke Univ. Leuven (Belgium)

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis, which kills 1.8 million annually. Mtb RNA polymerase (RNAP) is the target of the first-line antituberculosis drug rifampin (Rif). We report crystal structures of Mtb RNAP, alone and in complex with Rif, at 3.8–4.4 Å resolution. The results identify an Mtb-specific structural module of Mtb RNAP and establish that Rif functions by a steric-occlusion mechanism that prevents extension of RNA. Furthermore, we also report non-Rif-related compounds—Nα-aroyl-N-aryl-phenylalaninamides (AAPs)—that potently and selectively inhibit Mtb RNAP and Mtb growth, and we report crystal structures of Mtb RNAP in complex with AAPs. AAPs bind to a different site on Mtb RNAP than Rif, exhibit no cross-resistance with Rif, function additively when co-administered with Rif, and suppress resistance emergence when co-administered with Rif.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); Global Alliance for TB Drug Development

Grant/Contract Number:: GM041376; AI109713-8681

OSTI ID:: 1368240

Journal Information:: Molecular Cell, Vol. 66, Issue 2; ISSN 1097-2765

Publisher:: Cell Press - ElsevierCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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59 BASIC BIOLOGICAL SCIENCES
RNA polymerase
sigma factor
promoter
RNA polymerase-promoter open complex
RNA polymerase-promoter initial transcribing complex
RNA polymerase inhibitors
antituberculosis agents
rifampin
Nα-aroyl-N-aryl-phenylalaninamides
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Title: Structural Basis of Mycobacterium tuberculosis Transcription and Transcription Inhibition

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